The general objective of this project is to develop potent competive antagonists of oxytocin (OT) and to begin studies on the pharmacologic potential of these analogs for inhibiting parturition in rats. The antagonists will be designed by making isosteric substitutions that will preserve most of the steric, conformational and electronic similarities to the hormone and/or known best competive antagonists. Analogs will be evaluated by oxytocic, antidiuretic and pressor bioassays in the rat. Binding assays for the antagonists will be performed with receptors in rat uterine membranes to ascertain the contribution of receptor affinity to antagonist potency. Enzymatically resistant antagonists will be devised by substituting OT's natural amino acids with unnatural amino acids (eg, D-amino acids, etc) in order to inhibit peptide bond hydrolysis by degrading enzymes and to prolong the duration of OT action. The survival of the best antagonist in kidney and liver tissues will be studied in in vitro and in vivo and the half-life in the circulation, to evaluate the contribution of antagonist stability to biological potency. The most potent and specific OT antagonist will be tested for inhibition of milk let-down, in vivo uterine contractions and labor. The successful design of very potent antagonists would make possible basic studies on the role of OT in labor and the eventual testing in humans for prevention of premature labor.